Weinreb Amide Chemistry

At our recent Organic Process Research and Development conference (Budapest) we were treated to a number of excellent talks, one of which was given by Olivier Dirat (Pfizer).  The presentation featured some chemistry using a Weinreb amide and proposed a mechanism that could explain the formation of the N-methylamide impurity.

The common mechanism for the side reaction during Weinreb amide additions is outlined below:

However, the team at Pfizer also examined the O-t-butoxy version wherein there is no proton available for removal to release the aldehyde/ketone by-product and found that with this analogue they also obtained a similar 10-15% of the N-methylamide by-product.

Based on this result, they propose a single electron transfer mechanism as below.

Another interesting aspect of the talk was the use of t-butyl magnesium chloride as base which was shown not to add to the Weinreb amide.